Early longitudinal proteomic changes during sirolimus therapy in tocilizumab-refractory idiopathic multicentric Castleman disease.

To characterise early treatment-associated changes in circulating immune mediators following sirolimus initiation in patients with tocilizumab-resistant idiopathic multicentric Castleman disease (iMCD). As a predefined translational sub-analysis of a placebo-controlled exploratory trial, we performed longitudinal serum proteomic profiling using a RayBiotech L-1000 antibody array (∼1,000 proteins) in a sirolimus-treated patient with tocilizumab-resistant iMCD. Serum samples were obtained at baseline and at weeks 8, 12, and 16. Protein expression levels were normalised, log₂-transformed, and analysed for stepwise temporal changes. Pathway-level effects were assessed using gene set enrichment analysis (GSEA). Six immune mediators-CCR5, ICAM-1, RANTES, S100A8/A9, CD40 ligand, and OX40 ligand-showed consistent monotonic decreases from baseline through week 12. Heatmap visualisation of the top 80 dynamically regulated proteins confirmed a broader suppression of immune activation signatures. GSEA demonstrated significant negative enrichment of coagulation, complement, IFN-γ response, IL-6-JAK-STAT3 signalling, TNFα signalling via NF-κB, and MMP-driven extracellular matrix remodelling. Temporal analysis confirmed sustained downregulation of IFN-γ-inducible chemokines (CXCL9, CXCL10, CXCL11) and a broad panel of interferon-response mediators through weeks 12 and 16. Early and coordinated decreases in immune-inflammatory mediators were observed during sirolimus therapy in tocilizumab-resistant iMCD, extending beyond the IL-6 axis to encompass IFN-γ, TNF-α, and chemokine signalling. These findings are hypothesis-generating and provide a mechanistic rationale for mTOR inhibition as a potential disease-modifying strategy warranting evaluation in future controlled studies.